The transient receptor potential, vanilloid (TRPV), group 1 subfamily of channels includes four members: TRPV1, TRPV2, TRPV3 and TRPV4. TRPV channels are thermosensitive non- selective cation channels gated by a variety of endogenous ligands. TRPV1 agonists and antagonists are currently being tested for use in multiple disease states including pain. TRPV channel expression was originally reported in the peripheral nervous system; however growing evidence suggests that TRPV channels are also expressed in the brain. Little is known about how TRPV modulation and activation influences synaptic transmission in the brain. Our laboratory has recently shown that TRPV1 channels are essential for depression at synapses on GABAergic interneurons within the hippocampal CA1 region, a brain region important in learning and memory. Furthermore, my preliminary data suggests that TRPV3 channels are also required for this form of synaptic depression. The discovery of TRPV1 and TRPV3 as Ca2+ permeable cation channels in hippocampal neurons and their triggering of synaptic changes have important implications for how hippocampal circuits process information, thus modulating the neuronal network. We hypothesize that both TRPV1 and TRPV3 channels are necessary for synaptic depression of excitatory synapses on interneurons in the hippocampus, which may ultimately impact learning and memory mechanisms. Therefore, using electrophysiological and behavioral techniques we propose to characterize the significance of TRPV1 and TRPV3 channel regulation on synaptic transmission and how these channels influence sensory, emotive and cognitive processing. By characterizing this novel form of synaptic plasticity our findings will provide important basic information about hippocampal function and may prove to have direct clinical relevance as TRPV channel therapeutics continue to be developed. PUBLIC HEALTH RELEVANCE: TRPV1 and TRPV3 are channel proteins activated by various endogenous ligands and heat. Recently TRPV channels have been shown to be expressed in the hippocampus, a brain region important for learning and memory. Here we will test whether TRPV1 and TRPV3 channel activation is necessary for changes in brain synapses that may underlie aspects of learning or memory.